The discovery of the antiviral APOBEC3 (A3) proteins is regarded as one of the most therapeutically promising breakthroughs in HIV/AIDS molecular virology in the last decade. Several A3 proteins have the capacity to restrict HIV replication by incorporating into assembling viral particles, physically interfering with the progression of reverse transcription, and deaminating viral cDNA cytosines to uracils. The latter antiviral activity is the defining hallmark of A3-mediated restriction, explaining the genomic strand G-to-A mutations that are frequently observed in patient-derived viral sequences. Here, we will address two major questions. First, we will ask whether stable A3H haplotypes provide a barrier to HIV acquisition in instances where the transmitting virus originates from a person with an unstable A3H haplotype. Moreover, in individuals where the virus overcomes this barrier and transmission still occurs, we also ask how the virus adapts to efficiently counteract stable A3H and how this relates to disease progression. These experiments are motivated by preliminary data showing that stable A3H haplotypes potently restrict the replication of viruses with naturally occurring hypofunctional vif alleles. These studies have the potential to explain why some highly exposed individuals naturally resist viral infection. Second, we will ask whether HIV has additional mechanisms, independent of Vif, to counteract restriction by A3 proteins. This will be addressed through a series of vif-null virus adaptation experiments to restrictive pressures imposed by A3 proteins, followed by comprehensive analyses of the resulting mutations to deduce the underlying escape mechanisms. These experiments are anticipated to provide genetic portals into aspects of the restriction mechanism that are poorly understood such as A3 post-translational regulation, assembly, packaging, and encapsidation. Together, our studies on transmission could have immediate clinical implications, and our studies on Vif-independent resistance will provide novel mechanistic insights and have longer-term clinical implications as the field moves further toward the development of therapeutics such as Vif inhibitors that will be able to leverage this powerful innate immune defense system to block HIV replication and pathogenesis.

Public Health Relevance

HIV/AIDS is still a pandemic problem. Targeted innate immune therapies have yet to be developed against this virus. Fundamental research on the antiviral APOBEC3 enzymes will stimulate the development of innovative HIV/AIDS therapeutics that work by leveraging this innate immune defense system to extinguish virus replication.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI064046-13
Application #
9397503
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Mcdonald, David Joseph
Project Start
2004-12-01
Project End
2019-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
13
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Biochemistry
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Molan, Amy M; Hanson, Heather M; Chweya, Cynthia M et al. (2017) APOBEC3B lysine residues are dispensable for DNA cytosine deamination, HIV-1 restriction, and nuclear localization. Virology 511:74-81
Ikeda, Terumasa; Shimoda, Mayuko; Ebrahimi, Diako et al. (2017) Opossum APOBEC1 is a DNA mutator with retrovirus and retroelement restriction activity. Sci Rep 7:46719
Nakano, Yusuke; Misawa, Naoko; Juarez-Fernandez, Guillermo et al. (2017) HIV-1 competition experiments in humanized mice show that APOBEC3H imposes selective pressure and promotes virus adaptation. PLoS Pathog 13:e1006348
Harris, Reuben S; Anderson, Brett D (2016) Evolutionary Paradigms from Ancient and Ongoing Conflicts between the Lentiviral Vif Protein and Mammalian APOBEC3 Enzymes. PLoS Pathog 12:e1005958
Shaban, Nadine M; Shi, Ke; Li, Ming et al. (2016) 1.92 Angstrom Zinc-Free APOBEC3F Catalytic Domain Crystal Structure. J Mol Biol 428:2307-16
Anderson, Brett D; Harris, Reuben S (2015) Transcriptional regulation of APOBEC3 antiviral immunity through the CBF-?/RUNX axis. Sci Adv 1:e1500296
Richards, Christopher; Albin, John S; Demir, Özlem et al. (2015) The Binding Interface between Human APOBEC3F and HIV-1 Vif Elucidated by Genetic and Computational Approaches. Cell Rep 13:1781-8
Harris, Reuben S; Dudley, Jaquelin P (2015) APOBECs and virus restriction. Virology 479-480:131-45
Yoshikawa, Rokusuke; Takeuchi, Junko S; Yamada, Eri et al. (2015) Vif determines the requirement for CBF-? in APOBEC3 degradation. J Gen Virol 96:887-92

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